Congenital disorders of glycosylation (CDG)

CDGs comprise a clinically heterogeneous group of inherited metabolic diseases with highly variable age of onset and severity, ranging from lethal neonatal presentations to minimally symptomatic adults. Most patients present during early childhood with multisystem involvement. Although virtually any organ system can be affected, neurological manifestations are the most common and include developmental delay, hypotonia, intellectual disability, epilepsy, ataxia, peripheral neuropathy, and stroke-like episodes. Additional frequent features include feeding difficulties, failure to thrive and hypoglycemia. PMM2-CDG, the most common CDG subtype, is characterized by prominent neurological manifestations, including intellectual disability, cerebellar ataxia, hypotonia, and peripheral neuropathy, frequently accompanied by cardiac, hepatic, musculoskeletal, and coagulation abnormalities. Neurological symptoms are generally stable in adulthood, whereas skeletal complications such as kyphoscoliosis and osteoporosis may progress over time. While most CDGs are multisystem disorders, some exhibit predominantly single-organ involvement, affecting tissues such as the retina, brain, liver, skin, skeletal muscle, cartilage, neuromuscular junction, or hematopoietic system.

The estimated prevalence in European and African-American populations is 1/10,000.

To date, over 160 different types of CDG have been described. Advances in biochemical and genetic diagnostics have substantially improved CDG detection. While biochemical analyses remain important, next-generation sequencing has become a key diagnostic tool, enabling the identification of both known and novel CDG subtypes. Diagnosis often requires an extensive and complex diagnostic workup, resulting in multiple uncertainties regarding genetic counseling and disease prognosis. Early and accurate subtype diagnosis is essential, as specific therapeutic options are available for selected CDGs.

Most congenital disorders of glycosylation (CDGs) are inherited in an autosomal recessive manner, whereas a smaller number exhibit autosomal dominant inheritance, and a few are X-linked.

• Where CDGs are suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Park JH, Marquardt T. Treatment options in congenital disorders of glycosylation. Front Genet. 2021;12:735348. doi:10.3389/fgene.2021.735348. PMID:; PMCID: PMC8461064.